The adaptive immune response to mucosal pathogens is still poorly understood, limiting the development of new vaccines for important human pathogens such as the category B bioterrorism agent Salmonella. I propose to use newly developed reagents to examine the Salmonella-specific CD4 T cells activation and memory in the intestinal mucosa and systemic tissues. The specific aims of this proposal are: Aim 1. Determine whether differential expression of Salmonella proteins in different locations allows priming of site-specific CD4 T cells. Aim 2. Examine whether Salmonella-specific memory CD4 T cell development is impaired after rapid clearance of virulent bacteria. My preliminary data demonstrate that I can develop novel MHC class-II tetramer reagents to track the mucosal and systemic Salmonella-specific T cell response in vivo. My two specific aims will use cutting-edge technology, to examine the priming, and memory development of endogenous Salmonella- specific T cells for the first time. PUBLIC HEALTH RELEVANCE: Typhoid is a potentially fatal disease caused by oral Salmonella infection and recognized as a potential bioterrorist threat in the US. This proposal will examine the protective CD4 T cell response to this organism using a mouse model of Salmonella infection and newly developed immunological tools to detect mucosal and systemic responses. This proposal will therefore increase our understanding of how these protective CD4 T cells are activated and function in the face of mucosal bacterial infection.